DESCRIPTION: (adapted verbatim from the investigator's abstract) Neuroblastoma (NB) is the most common extra cranial solid tumor in children. The tumor is of neural crest origin, has a heterogeneous histopathology and often expresses markers of the sympathoadrenal (SA) lineage, including receptors for neurotrophins (NT). Absence of trkA expression, the receptor for nerve growth factor (NGF) directly correlates with poor prognosis. Consistent with these data, we showed that reconstitution of a functional NGF/trkA pathway reversed the tumorigenic phenotype in vitro and in vivo, thus underscoring the importance of NT's in NB oncogenesis and progression. We hypothesize that unresponsiveness of NB to NT's is rather the consequence of the undifferentiated state of the tumor, than genomic alterations and that NT sensitivity can be restored by agents controlling normal SA maturation. In line with this hypothesis, recent data obtained in our laboratory show that growth arrest and terminal differentiation of NB cells can be achieved by activating silenced NT receptor genes. Experiments outlined in Specific Aim #1 shall examine in detail extrinsic and intrinsic components regulating NB cell differentiation in vitro. Lack of animal models mimicking the course of the human NB disease have hampered the development of novel treatment modalities. Particularly, spontaneous metastasis does not occur in immune compromised animals bearing subcutaneous NB tumors. Recently, we were successful in developing spontaneous macro and micro metastases in mice by removing the primary NB tumor, mimicking a model of minimal residual disease. We shall characterize the dissemination of NB cells in this model and isolate cell populations with organ specific metastatic properties. Relapse of NB after treatment is the leading cause of death in patients. Micro metastases and/or prolonged tumor cell dormancy may in part be responsible for late recurrence. Induction of terminal differentiation by agents regulating normal SA maturation may offer an alternative to current post treatment protocols. Hence, experiments proposed in Specific Aim #3 shall investigate the potential of reagents identified in Specific Aim #1 to modulate the metastatic phenotype of NB cells using the new mouse model established in Specific Aim #2. Results obtained from the proposed experiments will define the potential usefulness of neurotrophic factors for treatment of NB in vivo.